According to the United States Renal Data System, focal and segmental glomerulosclerosis (FSGS) is the most common histopathological finding in primary nephrotic syndrome patients with end-stage renal disease (ESRD). Treatment options in primary forms of FSGS are limited, poorly tolerated, and fail to produce a sustained remission in as many as half of these patients. Moreover, primary FSGS often recurs after kidney transplantation, leading inexorably to graft failure in as many as 30% of cases. As such there is a large unmet need for novel pharmacotherapies to slow or prevent progression of renal failure in these diseases. TRPC6 channels are expressed at abnormally high levels in podocytes in primary FSGS and modulation of their function has been shown to affect the slit-diaphragm. Exposure to serum from patients with FSGS results in hyperactivation of podocyte TRPC6 channels in response to mechanical stimuli and a similar pattern is observed in a rat model of secondary FSGS. Moreover, research in mouse models has shown that knock-outs that eliminate glomerular TRPC6 expression reduce albuminuria evoked by chronic angiotensin or albumin overload. This and other data suggest that inhibition of TRPC6 channels represents a therapeutic strategy for this class of glomerular diseases. Algomedix has discovered and characterized a novel series of potent TRP6 antagonists with drug-like properties which block human TRPC6 channels. A unique feature of these novel compounds is that they block activation of rodent TRPC6 channels by Angiotensin II, OAG or mechanical activation with similar nanomolar IC50s. This research will expand on the initial active compounds in this series to develop a series of novel first-in-class antagonists, characterize their potency and selectivity in cell lines, test their ability to block human mutated TRPC6 channels known to cause familial FSGS, and examine their ability to inhibit endogenously expressed TRPC6 channels in podocytes. A key feature of these studies in an ex vivo model of podocytes will be to analyze antagonist activity using multiple modes of activation, including mechanical, which may be the most relevant for translation to clinical efficacy in FSGS. These studies will yield a lead and backup compounds ready for advancement to in vivo studies. In Phase 2 studies, the efficacy of the lead and backup compounds will be determined in well-characterized rodent models of glomerular kidney disease using chronic dosing in conjunction with pharmacokinetic, pharmacodynamic and safety studies.